Stable cream and lotion bases for lipophilic drug compositions

ABSTRACT

A cosmetically elegant, physically and chemically stable base in the form of an oil-in-water emulsion for use in cream and lotion lipophilic drug containing- pharmaceutical compositions containing at least one lipophilic drug and an effective amount of N-methyl-2-pyrrolidone is disclosed.

The present application is the United States national applicationcorresponding to International Application No. PCT/US90/07228, filed 14Dec. 1990, and designating the United States, which PCT application isin turn a continuation of U.S. application Ser. No. 07/453,564, filed 20Dec. 1989, now abandoned, the benefit of which applications is claimedpursuant to the provisions of 35 U.S.C. §§120, 363 and 365(C).

This invention relates to cosmetically elegant, chemically andphysicially stable topical cream and lotion bases and lipophilic drugcompositions containing an amount of N-methyl-2-pyrrolidone effective toenable penetration through the skin of lipophilic drugs, such assteroids and antimicrobials.

Topical application of drugs is the preferred mode of administration inmany instances to avoid side effects often found with systemicapplication of such drugs. Topical pharmaceutical compositions shouldpossess the following characteristics:

1) superior skin penetration with minimal skin irritation and/orsensitization;

2) chemical stability;

3) physical stability; and

4) cosmetic elegance.

One of the most serious problems which must be overcome in developing aneffective topical base for a pharmaceutical composition is penetrationof the drug into the skin. Good skin penetration is a particularlydifficult problem for lipophilic drugs exhibiting low water solubility,such as steroids and antimicrobials, especially antifungals andpentrants for such drugs are often added to lipophilic drug-containingcompositions.

Penetrants for drugs are known. U.S. Pat. No. 3,551,554 discloses use ofdimethyl sulfoxide and U.S. Pat. No. 4,316,893 discloses use of 1-loweralkyl substituted azacyclopentan-2-ones to enhance percutaneousadsorption of drugs. N-methyl-2-pyrrolidone is also a known penetrantfor drugs, but it has been found in our laboratories thatN-methyl-2-pyrrolidone breaks down emulsion systems such as creams andlotions. Thus, we are aware of no successful cream or lotion systemscontaining N-methyl-2-pyrrolidone. Creams and lotions, e.g.,oil-in-water emulsions, are particularly desirable bases for suchlipophilic drugs. In the course of developing the bases andpharmaceutical compositions of the present invention, we preparednumerous creams containing known drug penetration agents such asdimethyl sulfoxide and N-methyl pyrrolidone, but most of these creamsdid not have all of the desired characteristics necessary for anacceptable topical pharmaceutical formulation for a lipophilic drug.

Thus, there is still a need for a chemically and physically stable,cosmetically elegant topical cream and/or lotion base for a lipophilicdrug-containing pharmaceutical composition which allows effectivepenetration of the lipophilic drug through the skin with minimal skinirritation and/or sensitization.

SUMMARY OF THE INVENTION

We have surprisingly discovered that a chemically and physically stable,cosmetically elegant topical cream and lotion base for lipophilicdrug-containing pharmaceutical compositions which incorporates an amountof N-methyl-2-pyrrolidone effective to allow penetration of a lipophilicdrug through the skin with minimal skin irritation. Thus, this inventionprovides a base in the form of an oil-in-water emulsion for use in creamand lotion lipophilic drug-containing pharmaceutical compositionscontaining at least one lipophilic drug comprising (a) an amount ofN-methyl-2-pyrrolidone effective to enable a lipophilic drug topenetrate through the skin, (b) an aqueous phase comprising water and anamount of propylene glycol sufficient to at least partially solibilize alipophilic drug in the aqueous phase; and (c) an oil phase comprising anamount of mineral oil or diethyl sebacate effective to at leastpartially solubilize a lipophilic drug in the oil phase, (d) an amountof a surfactant system effective to stablize the emulsion formed fromthe oil phase and aqueous phase, (e) an occlusive agent, (f) apreservative, and optionally a silicon oil and wherein the pH of saidbase is in the range of about 4.0 to 7.0.

This invention also provides a topical cream and/or lotionpharmaceutical composition in the form of an oil-in-water emulsioncontaining at least one lipophilic drug and a base comprising (a) anamount of N-methyl-2-pyrrolidone effective to enable a lipophilic drugto penetrate through the skin, (b) an aqueous phase comprising water andan amount of propylene glycol sufficient to at least partiallysolubilize a lipophilic drug in the aqueous phase; and (c) an oil phasecomprising an amount of diethyl sebacate or mineral oil effective to atleast partially solubilize a lipophilic drug in the oil phase; (d) anamount of a surfactant system effective to stabilize the emulsion formedfrom the oil phase and aqueous phase; (e) an occlusive agent; and (f) apreservative, and wherein the pH of the composition is in the range ofabout 4.0 to 7.0.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred aspect of the invention, there is provided a base in theform of an oil-in-water emulsion for use in a cream lipophilicdrug-containing pharmaceutical composition comprising:

(a) about 25 to 100 mg/g of N-methyl-2-pyrrolidone;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 300 to 700 mg/g of purified water;

(d) about 20 to 120 mg/g of propylene glycol;

(e) about 15 to 65 mg/g of propylene glycol stearate;

(f) about 30 to 75 mg/g of a mixture of stearyl alcohol andceteareth-20;

(g) about 100 to 200 mg/g of white petrolatum;

(h) about 5 to 15 mg/g of benzyl alcohol; and

(i) about 5 to 20 mg/g of trimethylsiloxy-silicate; and wherein the pHof said base is adjusted to about 4.5 to about 6.5.

In another preferred aspect of this invention, there is provided a basefor use in a lotion lipophilic-drug containing pharmaceuticalcomposition in the form of an oil-in-water emulsion comprising:

(a) about 25 to 100 mg/g of N-methyl pyrrolidone;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 300 to 700 mg/g of purified water;

(d) about 20 to 120 mg/g of propylene glycol;

(e) about 15 to 65 mg/g of propylene glycol stearate;

(f) about 30 to 75 mg/g of a mixture of stearyl alcohol andceteareth-20;

(g) about 50 to 100 mg/g of white petrolatum;

(h) about 5 to 15 mg/g of benzyl alcohol; and

(i) about 5 to 20 mg/g of trimethylsiloxy-silicate; and wherein the pHof the purified water-containing phase is adjusted to about 5.5 to about6.5.

In another preferred aspect, this invention provides a topical cream andlotion pharmaceutical composition in the form of an oil-in-wateremulsion for application of a lipophilic drug to the skin comprising:

(a) about 0.5 to 20 mg/g of at least one lipophilic drug;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 50 to 200 mg/g of white petrolatum;

(d) about 15 to 65 mg/g of propylene glycol stearate;

(e) about 35 to 70 mg/g of a mixture of stearyl alcohol andceteareth-20;

(f) about 5 to 20 mg/g of a trimethylsiloxy-silicate;

(g) about 300 to 800 mg/g of purified water;

(h) about 20 to 120 mg/g of propylene glycol; and

(i) about 25 to 100 mg/g of N-methyl-2-pyrrolidone;

and wherein the pH of said composition is adjusted to a value in therange of about 4.5 to 6.5

In still another aspect, this invention provides a topical creampharmaceutical composition in the form of an oil-in-water emulsion fortreatment of inflammation comprising:

(a) about 0.5 to 1.5 mg/g of a lipophilic steroid drug selected frommometasone furoate, betamethasone diproprionate, betamethasone valeratealcolomethasone diproprionate, hydrocortisone and mixtures thereof;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 100 to 200 mg/g of white petrolatum;

(d) about 15 to 65 mg/g of propylene glycol strearate;

(e) about 30 to 75 mg/g of a 75:25 (w/w) mixture of stearyl alcohol andceteareth-20;

(f) about 5 to 20 mg/g of trimethylsiloxy-silicate;

(g) about 300 to 700 mg/g of purified water;

(h) 20 to 120 mg/g of propylene glycol; and

(i) about 5 to 15 mg/g of benzyl alcohol; and

(j) about 25 to 100 mg/g of N-methyl-2-pyrrolidone; and wherein the pHof said composition is adjusted to a value in the range of about 4.5 to6.5.

In a further aspect, this invention provides a topical lotionpharmaceutical composition in the form of an oil-in-water emulsion fortreatment of inflammation comprising:

(a) about 0.5 to about 1.5 mg/g of a lipophilic steroid drug selectedfrom mometasone furoate, betamethasone diproprionate, betamethasonevalerate alcomethasone diproprionate, hydrocortisone and mixturesthereof;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 50 to 100 mg/g of white petrolatum;

(d) about 15 to 65 mg/g of propylene glycol stearate;

(e) about 30 to 75 mg/g of a 75:25 (w/w) mixture of stearyl alcohol andceteareth-20;

(f) about 5 to 20 mg/g of trimethylsiloxy-silicate;

(g) about 400 to 800 mg/g of purified water;

(h) about 20 to 120 mg/g of propylene glycol;

(i) about 5 to 15 mg/g of benzyl alcohol; and

(j) about 25 to 100 mg/g of N-methyl-2-pyrrolidone; and wherein the pHof said composition is adjusted to a value in the range of about 4.5 to6.5.

In another preferred aspect of the present invention the provisionprovides a topical cream pharmaceutical composition in the form of anoil-in-water emulsion for treatment of inflammation comprising:

(a) about 5. to 15 mg/g of a lipophilic antifungal drug;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 100 to 200 mg/g of white petrolatum;

(d) about 15 to 65 mg/g of propylene glycol stearate;

(e) about 30 to 75 mg/g of a mixture of stearyl alcohol andCetreareth-20;

(f) about 5 to 20 mg/g of trimethylsiloxy-silicate;

(g) about 300 to 700 mg/g of purified water;

(h) about 20 to 120 mg/g of propylene glycol;

(i) about 5 to 15 mg/g of benzyl alcohol; and

(j) about 25 to 100 mg/g of N-methyl-2-pyrrolidone;

and wherein the pH of said composition is adjusted to a value in therange of about 4.5 to about 6.5.

The preferred lipophilic antifungal agents are clotrimazole andtolnaftate.

In still another preferred aspect, this invention provides a topicallotion pharmaceutical composition in the form of an oil-in-wateremulsion for treatment of inflammation comprising:

(a) about 5 to 15 mg/g of a lipophilic antifungal agent;

(b) about 20 to 90 mg/g of diethyl sebacate or mineral oil;

(c) about 50 to 100 mg/g of white petrolatum;

(d) about 15 to 65 mg/g of propylene glycol stearate;

(e) about 30 to 75 mg/g of a mixture of stearyl alcohol andCeteareth-20;

(f) about 5 to 20 mg/g of trimethylsiloxy-silicate;

(g) about 400 to 800 mg/g of purified water;

(h) about 20 to 120 mg/g of propylene glycol;

(i) about 5 to 15 mg/g of benzyl alcohol; and

(j) about 25 to 100 mg/g of N-methyl-2-pyrrolidone; and wherein the pHof said composition is adjusted to a valve in the range of about 4.5 toabout 6.5.

The preferred antifungal agents are clotrimazole and tolnaftate.

The topical cream bases and topical cream pharmaceutical compositionpreferably contain about 400 to about 700 mg/g of purified water.

We have surprisingly discovered that N-methyl-2-pyrrolidone (hereinafter M-pyrol) which has been found by us to disrupt cream structures bycausing a breakdown of the emulsion can be successfully used in a creamor lotion base to promote the enhancement of skin penetration oflipophilic drugs without causing a breakdown in the emulsion. Thepresent invention provides unique oil-in-water cream and lotion baseswhich possess a high degree of cosmetic elegance compared to otherconventional cream bases. Even though the bases of the present inventionincorporate M-pyrol as the penetrant for lipophilic drugs, the bases andpharmaceutical compositions of the present invention are physically andchemically stable at elevated temperature for periods as long as 3months to 2 years while simultaneously providing support skinpenetration for a variety of lipophilic drugs.

The term "lipophilic drug" as used herein includes steroids,anti-inflammatory agents, antifungal agents and carthartic agents.

Typical suitable steroids include mometasone furoate, betamethasone andits esters especially betamethasone diproprionate, betamethasonevalerate and betamethasone divalerate, alcolomethasone, and its esters,especially alcolomethasone diproprionate as well as other lipophilicphysiologically active steroids which are well known to those skilled inthe art.

The pharmaceutical compositions of the present invention incorporatinglipophilic steroids are useful for treating inflammatory conditions.

The preferred steroids for use in the pharmaceutical compositions of theinvention for treating inflammation includes about 0.5 to 1.5 mg/g of alipophilic steroid drug selected from mometasone furoate, betamethasonediproprionate, betamethasone valerate, alcolomethasone diproprionate,hydrocortisone and mixtures thereof.

The pharmaceutical compositions of the present invention are also usefulfor treating mild eczema, for example, by applying a cream or lotion ofanti-inflammatory agents such as fluocinolone acetonide or itsderivatives, hydrocortisone, triamcinolone acetonide, indomethacin,salicylates or phenylbutazone dispersed in bases of the presentinvention to the affected area.

Lipophilic antifungal agents such as, for example, clotrimazole and aswell as other lipophilic antifungal agents well known to those skilledin the art which may be dispersed in the vehicles described herein andtopically applied to affected areas of the skin. For example, antifungalagents so applied are carried into the skin to the location of thefungus causing the infection, and thereby successfully treatfungus-caused skin problems. These agents, thus applied, not onlypenetrate more quickly than when applied in the vehicles of the priorart, but additionally enter the animal tissue in high concentrations andare retained for substantially longer time periods whereby a far moresuccessful treatment is effected.

For example, the pharmaceutical compositions of the present inventionmay also be employed in the treatment of fungus infections on the skincaused by Candida and dermatophytes which cause athletes foot orringworm, by dispersing tolnaftate or similar lipophilic antifungalagents such as clotrimazole in a base of the present invention andapplying it to the affected area.

The pharmaceutical compositions of the present invention are also usefulin treating skin problems, such as for example, herpes simplex, whichmay be treated by a solution of iododeoxyuridine dispersed in a base ofthe present invention, or such problems as warts which may be treatedwith carthartic agents such as podophylline dissolved in one of thebases of this invention. Skin problems such as psoriasis may be treatedby topical application of a cream or lotion of a conventional topicalsteroid in one of the bases of this invention or by treatment withtheophylline or antagonists of beta-adrenergic blockers such asisoproterenol in one of the bases of the present invention. Scalpconditions such as alopecia areata may be treated more effectively byapplying lipophilic steroids such as triamcinolone acetonide dispersedin one of the bases of this invention directly to the scalp.

The amount of M-pyrol found effective to enable an effective amount of alipophilic drug to penetrate through the skin is in the range of about 5to about 15 preferably about 5 to about 10% and more preferably about 5%by weight of the pharmaceutical composition.

The oil phase contains an effective amount of diethyl sebacate ormineral oil. Surprisingly, we found that use of diethyl sebacate ormineral oil in the amount of about 20 to 90 mg/g, preferably an amountof about 35 mg/g of the bases or pharmaceutical compositions of thepresent invention allowed use of lower amounts (e.g., about 5-10, morepreferably about 5 weight %) of M-pyrol. The use of the diethyl sebacateis preferred.

Typical suitable surfactant systems found effective to stabilize theoil-in-water emulsions formed by the oil phase and aqueous phase of thebases and pharmaceutical compositions of the present invention includeabout 30 to 75 mg/g of a mixture of stearyl alcohol and ceteareth-20 incombination with about 15 to 65 mg/g of a nonionic surfactants selectedfrom propylene glycol stearate, glyceryl monostearate, PEG-1000monocetyl ether, glyceryl monostearate, sorbitan monostearate andpolysorbate-60. Use of about 15-65 mg/g, preferably about 40 mg/g ofpropylene glycol stearate in combination with about 30-75 mg/g,preferably about 55 mg/g of a of stearyl alcohol and ceteareth-20mixture of stearyl alcohol and ceteareth-20 is available from AmercholCorp, Edison N.J. 08812 under the tradename, Promulgen G) as thesurfactant system is preferred.

Typical suitable preservatives include benzyl alcohol, potassiumsorbate, sorbic acid and sodium benzoate as well as other preservatives,e.g. the paraben, e.g. methylparaben which are normally added to theaqueous phase. Use of about 5 to about 15 mg/g, preferably about 10 mg/gof benzyl alcohol is preferred.

Silicon oils may be incorporated into the formulations of the presentinvention to enhance cosmetic elegance, especially to provide a creamwith a so-called vanishing cream-like appearance to the bases andpharmaceutical compositions of the present invention. Typical suitablesilicon oils include silicon oils approved for use in cosmetics andpharmaceuticals. The preferred silicon oil for the present invention isdimethicone (which is a mixture of fully methylated linear siloxanepolymers and blocked with trimethylsiloxy units and has the common name"trimethylsiloxy-silicate") in an amount of about 5 to about 20 mg/g,preferably about 10 mg/g of the bases and pharmaceutical composition ofthe present invention.

The pH of the pharmaceutical composition of the present invention may bein the range of about 4.0 to about 7.0, and the precise pH range dependsupon the lipophilic drug or drugs present. Thus, the preferred pH rangeis (a) about 5.5 to 6.5 when only a lipophilic antifungal such asclotrimazole is present; (b) about 4.0 to 5.0 when a lipophilic steroidsuch mometasone furoate is present; and (c) in the range of about 4.5 to6.5, more preferably about 5.5 to 6.5 and most preferably about 6.0 whena mixture of a lipophilic steroid such as mometasone furoate and alipophilic antifungal such as clotrimazole is present.

Typical suitable buffer systems which maintain the pH of the bases andpharmaceutical compositions of the present invention in the range of 5.5to 6.5 include sodium phosphate monobasic/sodium phosphate dibasic, andcitrate-phosphate.

The bases are emulsions for use in a cream and/or lotion pharmaceuticalcompositions which are also in the form of emulsions of the presentinvention as well as the pharmaceutical compositions of the presentinvention. Such bases and compositions are manufactured in aconventional manner by thoroughly mixing the ingredients at ambient orelevated temperatures. Preferably the lipophilic drug or mixtures oflipophilic drugs are added to a small portion of the emulsion of the oiland water phases. The ingredients are thoroughly mixed so that theproduct is homogeneous. Processing equipment suitable for preparing thecream are known in the art and include colloid mills, homogenizers,roller mills, propeller mixers and the like.

General Experimental

All ingredients are U.S.P. grade and all percentages are by weight.Definitions of components whose chemical composition is not immediatelyclear from the name used, such as "Ceteareth-20" and "Promulgen-G", maybe found in the CTFA Cosmetic Ingredients Dictionary, 3rd Edition,published by Cosmetic Toiletry and Fragrance Association, Inc.,Washington, D.C.

The following examples illustrate the bases and compositions of thepresent invention. It will be apparent to those skilled in the art thatmany modifications thereof may be practical without departing from thepurpose and intent of this invention.

DESCRIPTION OF TEST PROCEDURES

1. Physical Stability

Samples of the formulations were evaluated initially and/or after beingstored at 35° C. or 40° C. for short periods of time e.g., up to 4 weeksby measuring for the following parameters:

(1) breakdown of the emulsion system (separation into separate layers);

(2) color change;

(3) change in viscosity;

(4) change in visual appearance.

Only formulations which did not separate (initially or after shortperiods) at elevated temperatures of 35° C. or 40° C. into separatelayers or did not exhibit a change in color or viscosity or visualappearance were considered physically stable.

2. Vasoconstrictor Scores

The local anti-inflammatory activity of the steroid-containingpharmaceutical compositions of the present invention were tested by thevasoconstrictor assay described by McKenzie and Stoughton, Arch.Dermatol., (1962) Vol. 86, 608.

Sixteen (16) to thirty-two (32) subjects from a pool of healthyvolunteers who met certain selection criteria were selected for eachstudy. No individual was used more frequently than once every two weeks.

Four sites, each approximately 2 cm in diameter and at least 1 cm apart,were delineated on the flexor surface of each of the subject's forearms,giving a total number of eight sites per subject. Ten (10) mg of each ofthe formulations tested per study were randomnly applied to these sites,an equal number of times.

The four sites on each arm were then covered with a protective plasticshield. Six and one half hours later the shields were removed, the testsites were washed with soap and water. Approximately 1/2 and 18 hoursafter removal of the shields, (7 and 24 hours after initial applicationof the test materials), the sites were examined and the degree ofblanching (vasoconstriction) was rated as follows: No blanching--0; mildblanching--1; moderate blanching--2 and strong blanching--3.

EXAMPLE 1

This example illustrates the effect of various known drug penetrationenhancers (dimethyl sulfoxide, triacetin, solketal, M-pyrol and oleylalcohol) to enhance the skin penetration of mometasone furoate presentin various cream bases.

    ______________________________________                                        Ingredients                mg/g                                               ______________________________________                                        BASE A                                                                        Mometasone Furoate, Micronized                                                                           1                                                  Propylene Glycol USP       100                                                Drug Penetration Enhancers*                                                                              100                                                Mineral Oil USP            60                                                 White Petrolatum USP       150                                                Cetostearyl Alcohol NF     72                                                 PEG-1000, Monocetyl Ether  22.5                                               Benzyl Alcohol             10                                                 Sodium Phosphate Monobasic Monohydrate USP                                                               2.65                                               Phosphoric Acid NF         0.62                                               Water Purified USP  q.s.   481.83                                             BASE B                                                                        Mometasone Furoate Micronized                                                                            1                                                  Olive Oil                  200                                                Oleyl Alcohol**            50                                                 Propylene Glycol USP       100                                                Isopropyl Myristate        10                                                 White Petrolatum USP       150                                                Stearyl Alcohol and Ceteareth-20                                                                         80                                                 PEG-1000, Monocetyl Ether  24                                                 Sodium Phosphate Monobasic Monohydrate USP                                                               2.65                                               Phosphoric Acid NF         0.02                                               Water Purified USP  q.s.   382.33                                             DIPROSONEG Ointment, 0.05%.sup.1                                              Betamethasone diproprionate, Micronized                                                                  0.64***                                            Mineral Oil, USP           50.00                                              White Petrolatum, USP      949.36                                                                        1.0 g                                              ______________________________________                                         *dimethylsulfoxide, triacetin, solketal, Mpyrol.                              **Drug Penetrant                                                              ***Equivalent to 0.5 mg/g of Betamethasone                                    .sup.1 Available from ScheringPlough Corporation, Kenilworth, New Jersey.

The five formulations containing the five drug penetration enhancerslisted above were evaluated for vasoconstrictor activity, cosmeticelegance and physical stability and compared to those for DIPROSONEOintment. The results are reported in the following Table I.

                  TABLE I                                                         ______________________________________                                                     7 Hrs. Vaso-                                                                  constrictor                                                                              Cosmetically                                                                             Physically                                 Drug Penetrant                                                                             Score.sup.1                                                                              Elegant    Stability                                  ______________________________________                                        Dimethyl Sulfoxide*                                                                        59         une;egant  unstable                                   Triacetin*   69         "          "                                          Solketal*    29         "          "                                          M-pyrol*     98         "          "                                          Oleyl Alcohol**                                                                            44         "          "                                          Diprosone Ointment,                                                                        100        elegant    stable                                     0.05%                                                                         ______________________________________                                         .sup.1 Mean score of 24 subjects; expressed as a % of Diprosone Ointment,     0.05%.                                                                        *in Base A                                                                    **in Base B                                                              

EXAMPLE 2

This example illustrates effect of the variation of M-pyrolconcentration in a base containing mineral oil on the vasoconstrictoractivity

    ______________________________________                                        Ingredients                 mg/g                                              ______________________________________                                        FORMULATION 2A (5% M-pyrol)                                                   Mometasone Furoate, Micronized                                                                            1                                                 Mineral Oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     50                                                White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30                                                Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF          0.02                                              Water Purified USP          524.33                                            FORMULATION 2B (10% M-pyrol)                                                  Mometasone Furoate Micronized                                                                             1                                                 Mineral oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     100                                               White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30                                                Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF          0.02                                              Water Purified USP          474.33                                            FORMULATION 2C (15% M-pyrol)                                                  Ingredients                                                                   Mometasone Furoate Micronized                                                                             1                                                 Mineral oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     iso                                               White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30,                                               Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF          0.02                                              Water Purified USP          424.33                                            FORMULATION 2D (20% M-pyrol)                                                  Mometasone Furoate Micronized                                                                             1                                                 Mineral Oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     200                                               White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30                                                Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF          0.02                                              Water Purified USP          374.33                                            ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        EFFECT OF M-PYROL LEVEL ON                                                    VASOCONSTRICTOR ACTIVITY                                                                         7 Hrs. Vaso-                                                         Conc.    constrictor                                                                              Cosmetic                                                                             Physical                                 Formulation                                                                             M-pyrol  Score.sup.1                                                                              Elegant                                                                              Stability                                ______________________________________                                        2A         5       80         inelegant                                                                            unstable                                 2B        10       86         "      "                                        2C        15       100        "      "                                        2D        20       82         "      "                                        ELOCON ®                                                                            --       100        elegant                                                                              stable                                   Cream.sup.2                                                                   ______________________________________                                         .sup.1 Mean score of 24 subjects; expressed as a % of ELOCON Cream.           .sup.2 Tradename of a mometasone furoate cream, 0.1% available from           ScheringPlough Corporation, Kenilworth, NJ.                              

EXAMPLE 3

This example illustrates the effect of the surfactant system on thecosmetic elegance and physical and chemical stability of a basecontaining M-pyrol.

    ______________________________________                                        Ingredients                 mg/g                                              ______________________________________                                        FORMULATION 3A                                                                Mometasone Furoate, Micronized                                                                            1                                                 Mineral Oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     100                                               White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30                                                Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF          0.02                                              Water Purified USP          474.33                                            FORMULATION 3B                                                                Mometasone Furoate Micronized                                                                             1                                                 Mineral Oil USP             60                                                Propylene Glycol USP        100                                               M-pyrol                     150                                               White Petrolatum USP        150                                               Cetostearyl Alcohol NF      72                                                Benzyl Alcohol              10                                                PEG-1000, Monocetyl Ether   30                                                Sodium Phosphate Monobasic Monohydrate USP                                                                2.65                                              Phosphoric Acid NF.sup.1    0.02                                              Water Purified USP          424.33                                            FORMULATION 3C                                                                Mometasone Furoate Micronized                                                                             0.5                                               Clotrimazole Micronized     10                                                Mineral Oil USP             60                                                White Petrolatum #4 USP     150                                               Propylene glycol stearate   40                                                Stearyl alcohol and Ceteareth-20                                                                          35                                                Propylene glycol USP        100                                               Benzyl Alcohol              10                                                Sodium Phosphate dibasic USP                                                                              0.35                                              Sodium Phosphate monobasic USP                                                                            5                                                 M-pyrol                     150                                               Purified Water USP          439.15                                            ______________________________________                                    

Procedure for Preparing Formulations 3A and 3B

1. Charge mineral oil, white petrolatum, cetostearyl alcohol andPEG-1000 monocetyl ether into a suitable jacketted container. Heat themixture to melt at 65°-70° C.

2. In a separate container, dissolve sodium phosphate monobasicmonohydrate and phosphoric acid in water at 65°-70° C.

3. Add benzyl alcohol to the water solution in Step 2 and mix well.

4. At 65°-70° C. charge the aqueous phase (Step 3) to oil phase (Step 1)and mix well to emulsify. Cool to 30°-35° C. with appropriate agitation.

5. Dissolve mometasone furoate into the M-pyrol.

6. Add the mixture Step 5 to that of Step 4 and mix appropriately whilecooling to room temperature.

Procedure for Preparing Formulation 3C

1. In a stainless steel bowl, weigh the white petrolatum, propyleneglycol stearate, stearyl alcohol and Ceteareth-20 and heat the admixtureto melt (65°-70° C.).

2. Disperse mometasone furoate in mineral oil with heat. When it isdissolved, add to Step 1 and mix.

3. Into a separate container, weigh the purified water, propyleneglycol, M-pyrol and benzyl alcohol. Heat the admixture to 65°-70° C.with mixing.

4. Add Step 3 to Step 1 and homogenize the batch with appropriate mixingfor approximately ten minutes. Start the so-formed emulsion to cool.

5. At 45° C., withdraw an adequate amount of emulsion (Step 4) to slurryclotrimazole in a slurry container and rinse slurry container.

6. Slurry the clotrimazole with a portion of the emulsion from Step 5and add to the admixture of Step 3. Mix well to disperse.

7. Rinse the slurry container with the remaining portion of emulsion ofStep 5 and charge rinses to Step 5. Mix well.

8. Adjust the pH of the so-formed emulsion to 5.9 ±0.1 with phosphatebuffer solution.

9. Transfer the emulsion to an appropriate mixer and continue to mix.Cool to RT to form a cream.

10. Fill the cream into the appropriate packages.

Formulations 3A to 3C were compared to ELOCON® Cream as described above.The results are reported in Table III.

                  TABLE III                                                       ______________________________________                                        EFFECT OF M-PYROL LEVEL ON                                                    VASOCONSTRICTOR ACTIVITY                                                                         7 Hrs. Vaso-                                                         M-pyrol  constrictor                                                                              Cosmetic                                                                             Physical                                 Formulation                                                                             %        Score.sup.1                                                                              Elegant                                                                              Stability                                ______________________________________                                        3A        10       115        inelegant                                                                            unstable                                 3B        15       111        "      "                                        3C.sup.2  15        90.sup.2  elegant                                                                              stable                                   ELOCON ®                                                                            --       100        "      "                                        Cream 0.1%                                                                    ______________________________________                                         .sup.1 Mean score of 24 subjects; expressed as a % of Elocon Cream, 0.1%.     .sup.2 Lower Vasoconstrictor score due to fact that Formulation 3C            contained only 1/2 the amoumt of clotrinazole present in Formulations 3A      and 3B.                                                                  

EXAMPLE 4

This example provides two cream formulations containing mineral oil andexhibiting high vasoconstrictor scores, which formulation, however, werephysically unstable.

    ______________________________________                                        Ingredients           mg/g                                                    ______________________________________                                        CREAM FORMULATION 4A                                                          Mometasone Furoate Micronized                                                                       0.5                                                     Clotrimazole Micronized                                                                             10                                                      Mineral Oil USP       60                                                      White Petrolatum #4 USP                                                                             150                                                     Propylene glycol stearate                                                                           40                                                      Stearyl alcohol and Ceteareth-20                                                                    35                                                      Propylene glycol USP  100                                                     Benzyl Alcohol        10                                                      Sodium Phosphate Monobasic USP                                                                      2.65                                                    N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    150                                                     Purified Water USP    441.85                                                  CREAM FORMULATION 4B                                                          Mometasone Furoate Micronized                                                                       1                                                       Mineral Oil USP       60                                                      White Petrolatum #4 USP                                                                             150                                                     Propylene Glycol Stearate                                                                           40                                                      Stearyl alcohol and Ceteareth-20                                                                    35                                                      Propylene glycol USP  100                                                     Benzyl Alcohol NF     10                                                      Phosphoric Acid NF    0.02                                                    Sodium Phosphate Monobasic USP                                                                      2.65                                                    N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    150                                                     Purified Water USP    451.33                                                  ______________________________________                                    

Procedure

1. Charge white petrolatum, propylene glycol stearate, stearyl alcoholand Ceteareth-20, into a suitable jacketted container. Heat thematerials to 65°-70° C. while mixing.

2. Charge purified water, propylene glycol, N-methyl-2-pyrrolidone andbenzyl alcohol into a suitable jacketted container. Heat the mixture to65°-70° C. while mixing.

3. Charge the mixture of Step 2 to the mixture of Step 1. Mix with anappropriate homogenizer for about 10 minutes. Check the pH. Ifnecessary, adjust pH to 5.6 ±0.1 with a 1% (w/v) solution of eitherphosphoric acid or sodium hydroxide. While mixing the batch, cool thebatch to 30°-35° C.

4. Remove an adequate amount of the emulsion of Step 3 and charge itinto an appropriate container. Mix the emulsion with the clotrimazolemicronized, and mometasone furoate micronized to form a slurry.

5. Add the slurry to the batch of Step 3. While mixing, the so-formedbatch maintain the batch at approximately 30° C.

6. Check the pH of the batch. If necessary, adjust pH to 5.9 ±0.2 with a1% (w/v) solution of either phosphoric acid or sodium hydroxide. Bringthe batch to final weight with purified water. Mix until homogeneous.

7. Cool the batch to room temperature (approximately 25° C.).

Cream formulations 4A and 4B were evaluated compared to ELOCON® Creamcontaining 0.1% mometasone furoate in accordance with procedures ofExamples 1-3. The results are provided in Table IV.

                  TABLE IV                                                        ______________________________________                                                       M-Pyrol   7 Hrs.                                               Formulation    (%)       Vasoconstrictor Score*                               ______________________________________                                        4A**           15         87**                                                4B**           15        110**                                                ELOCON ® Cream 0.1%                                                                      --        100                                                  ______________________________________                                         *Mean score of 24 subjects; expressed as a % of ELOCON Cream, 0.1%.           **Physical unstable at 35° C. after 1 month.                      

EXAMPLE 5

This example illustrates various preferred cream bases of the presentinvention containing diethyl sebacate.

    ______________________________________                                                                      Range                                           Ingredient            mg/g    mg/g                                            ______________________________________                                        Diethyl Sebacate      35       20-90                                          White Petrolatum #4   150     100-200                                         Propylene glycol stearate                                                                           40      15-65                                           Stearyl alcohol & Ceteareth-20*                                                                     55      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               Trimethylsiloxy silicate                                                                            10       5-20                                           N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         ______________________________________                                         *PROMULGEN-G                                                             

Method of Manufacture

1. In a stainless steel bowl, weight the white petrolatum, propyleneglycol stearate, diethyl sebacate, stearyl alcohol and ceteareth-20 andtrimethylsiloxy silicate. Heat the mixture to melt (65°-70° C.).

2. Into a separate container, weigh the purified water, propyleneglycol, N-methyl-2-pyrrolidone and benzyl alcohol. Heat the mixture to65°-70° C. with mixing.

3. Add Step 2 to Step 1 and homogenize the batch with appropriate mixingfor approximately ten minutes.

4. Adjust pH to 5.9 ±0.2 with phosphoric acid, or a sodium hydroxidesolution.

5. Transfer the batch of step 4 to an appropriate mixer and continue tomix.

EXAMPLE 6

This example illustrates preferred cream and lotion pharmaceuticalformulations of the present invention.

    ______________________________________                                                                      Range                                           Ingredient            mg/g    mg/g                                            ______________________________________                                        Vanishing Cream                                                               Mometasone Furoate Micronized                                                                       1       0.5-1.5                                         Clotrimazole Micronized                                                                             10       5-15                                           Diethyl Sebacate      35      20-90                                           White Petrolatum #4   150     100-200                                         Propylene glycol stearate                                                                           40      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      55      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               Trimethylsiloxy-silicate                                                                            10       5-20                                           N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         Lotion                                                                        Mometasone Furoate Micronized                                                                       1       0.5-1.5                                         Clotrimazole          10       5-15                                           Diethyl sebacate      35      20-90                                           White Petrolatum #4   100      50-100                                         Propylene glycol stearate                                                                           25      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      25      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Trimethylsiloxy silicate                                                                            10       5-20                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         ______________________________________                                         *Used to adjust pH to 5.9 to ±0.1.                                    

Method of Preparation of Vanishing Cream

1. In a stainless steel bowl, weigh the white petrolatum, propyleneglycol stearate, stearyl alcohol & Ceteareth-20, diethyl sebacate andtrimethylsiloxy silicate. Heat to melt (65°-70° C.).

2. Into a separate container, dissolve sodium phosphate monobasic andsodium phosphate dibasic in the purified water.

3. Add propylene glycol, N-methyl-2-pyrrolidone and benzyl alcohol tothe mixture of step 2. Heat the so-formed mixture to 65°-70° C. withmixing.

4. Add Step 3 to Step 1 and homogenize the batch with appropriate mixingfor approximately ten minutes. Cool it to 30° to 35° C.

5. At 30°-35° C., add to step 4. The mometasone furoate and clotrimazoleand mix until a homogeneous emulsion is formed and then cool theso-formed emulsion to room temperature.

6. Check pH and if necessary adjust pH to 5.9 ±0.1 with phosphoric acidor sodium hydroxide solution.

7. Transfer to an appropriate mixer and continue to mix until creamemulsion is formed.

8. Fill the cream emulsion into the appropriate packages.

The lotion was formulated in a manner analogous to that of the cream.

The lotion and cream exhibited high vasoconstrictor scores and werecosmetically elegant and physically and chemically stable after storageat 35° and 40° C. for 2 years.

EXAMPLE 7

This example illustrates preferred cream and lotion pharmaceuticalformulations of the present invention containing mometasone furoatemicronized as a preferred lipophilic steroid and prepared in accordancewith the procedure of Example 6 except no clotrimazole was added in step5. Similar cream and lotion formulations containing betamethasonediproprionate, betamethasone valerate or alcolomethasone diproprionatemay be prepared in an analogous manner.

    ______________________________________                                                                      Range                                           Ingredient            mg/g    mg/g                                            ______________________________________                                        Vanishing Cream                                                               Mometasone Furoate Micronized                                                                       1       0.5-1.5                                         Diethyl Sebacate      35      20-90                                           White Petrolatum #4   150     100-200                                         Propylene glycol stearate                                                                           40      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      55      30-75                                           Propylene glycol      50      20-120                                          Benzyl alcohol        10       5-15                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               Trimethylsiloxy-silicate                                                                            10       5-20                                           N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water   q.s. 1 g     300-700                                         Lotion                                                                        Mometasone Furoate Micronized                                                                       1       0.5-1.5                                         Diethyl sebacate      35      20-90                                           White Petrolatum #4   100      50-100                                         Propylene glycol stearate                                                                           25      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      25      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Trimethylsiloxy silicate                                                                            10       5-20                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50      25-100                                          Purified Water q.s.   1 g     300-700                                         ______________________________________                                    

EXAMPLE 8

This example illustrates preferred cream and lotion pharmaceuticalformulations of the present invention containing clotrimazole as thepreferred lipophilic antifungal and prepared in accordance with theprocedure of Example 6 except that only clotrimazole is added in step 5.A similar cream and lotion formulation could also be prepared bysubstituting tolnaftate for clotrimazole.

    ______________________________________                                                                      Range                                           Ingredient            mg/g    mg/g                                            ______________________________________                                        Vanishing Cream                                                               Clotrimazole Micronized                                                                             10       5-15                                           Diethyl sebacate      35      20-90                                           White Petrolatum #4   150     100-200                                         Propylene glycol stearate                                                                           40      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      55      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               Trimethylsiloxy-silicate                                                                            10       5-20                                           N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         Lotion                                                                        Clotrimazole          10       5-15                                           Diethyl sebacate      35      20-90                                           White Petrolatum #4 100                                                                              50-100                                                 Propylene glycol stearate                                                                           25      15-65                                           Stearyl alcohol Ceteareth-20*                                                                       25      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Trimethylsiloxy silicate                                                                            10       5-20                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         ______________________________________                                         *Used to adjust pH to 5.5 to 6.5.?                                       

EXAMPLE 9

This example illustrates preferred cream and lotion pharmaceuticalformulations of the present invention prepared in accordance with theprocedure of Example 6 except that mineral oil is added in step 1 inplace of diethyl sebacate. Similar cream and lotion formulation couldalso be prepared by substituting for mometasone furoate another steroidsuch as betamethasone diproprionate, betamethasone valerate oralcolomethasone diproprionate and substituting for the clotrimzoleanother antifungal such as tolnaftate

    ______________________________________                                                                      Range                                           Ingredient            mg/g    mg/g                                            ______________________________________                                        Vanishing Cream                                                               Mometasone Furoate Micronized                                                                       1       0.5-1.5                                         Clotrimazole Micronized                                                                             10       5-15                                           Mineral Oil USP       35      20-90                                           White Petrolatum #4   150     100-200                                         Propylene glycol stearate                                                                           40      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      55      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               Trimethylsiloxy-silicate                                                                            10       5-20                                           N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         Lotion                                                                        Mometasone Furoate micronized                                                                       1       0.5-1.5                                         Clotrimazole          10       5-15                                           Mineral Oil USP       35      20-90                                           White Petrolatum #4   100      50-100                                         Propylene glycol stearate                                                                           25      15-65                                           Stearyl alcohol & Ceteareth-20                                                                      25      30-75                                           Propylene glycol      50       20-120                                         Benzyl alcohol        10       5-15                                           Trimethylsiloxy silicate                                                                            10       5-20                                           Sodium phosphate monobasic                                                                          1.5*    *                                               Sodium phosphate dibasic                                                                            0.1*    *                                               N-Methyl-2-Pyrrolidone (M-pyrol)                                                                    50       25-100                                         Purified Water  q.s.  1 g     300-700                                         ______________________________________                                         *Used to adjust pH to 5.5 to 6.5.                                        

Method of Preparation of Vanishing Cream

1. In a stainless steel bowl, weigh the white petrolatum, propyleneglycol stearate, stearyl alcohol & Ceteareth-20, mineral oil andtrimethylsiloxy silicate. Heat the mixture to melt (65°-70° C.).

2. Into a separate container, dissolve sodium phosphate monobasic andsodium phosphate dibasic in the purified water.

3. Add propylene glycol, N-methyl-2-pyrrolidone and benzyl alcohol tostep 2. Heat the mixture to 65°-70° C. with mixing.

4. Add Step 3 to Step 1 and homogenize the batch with appropriate mixingfor approximately ten minutes. Cool the batch to 30° to 35° C.

5. At 30°-35° C., add to step 4 the mometasone furoate and clotrimazoleand mix until a homogeneous emulsion is formed and then cool theso-formed emulsion to room temperature.

5. Check pH and if necessary adjust pH to 5.9 ±0.1 with phosphoric acidor sodium hydroxide solution.

7. Transfer the emulsion to an appropriate mixer and continue to mixuntil a cream emulsion is formed.

8. Fill the cream emulsion into the appropriate packages.

The lotion is formulated in a manner analogous to that of the creamemulsion formulations.

The lotion and cream are expected to exhibit high vasoconstrictor scoresand to be physically and chemically stable after prolonged storage at25° and 35° C.

What is claimed is:
 1. A topical cream pharmaceutical compositioncomprising:(a) 0.5 to 2.0 mg/g of at least one lipophilic steroid orantifungal drug; (b) 20 to 90 mg/g of diethyl sebacate or mineral oil;(c) 100 to 200 mg/g of white petrolatum; (d) 15 to 65 mg/g of propyleneglycol stearate; (e) 30 to 75 mg/g of a mixture of stearyl alcohol andCeteareth-20; (f) 5 to 20 mg/g of trimethylsiloxy-silicate; (g) 300 to700 mg/g of purified water; (h) 20 to 120 mg/g of propylene glycol; (i)5 to 15 mg/g of benzyl alcohol; and (j) 25 to 100 mg/g ofN-methyl-2-pyrrolidone; and wherein the pH of said composition isadjusted to a value in the range of 4.5 to 6.5.
 2. A topical lotionpharmaceutical composition comprising:(a) 0.5 to 2.0 mg/g of at leastone lipophilic steroid or antifungal drug; (b) 20 to 90 mg/g of diethylsebacate or mineral; (c) 50 to 100 mg/g of white petrolatum; (d) 15 to65 mg/g of propylene glycol stearate; (e) 30 to 75 mg/g of a mixture ofstearyl alcohol and Ceteareth-20; (f) 5 to 20 mg/g oftrimethylsiloxy-silicate; (g) 400 to 800 mg/g of purified water; (h) 20to 120 mg/g of propylene glycol; (i) 5 to 15 mg/g of benzyl alcohol; and(j) 25 to 100 mg/g of N-methyl-2-pyrrolidone; and wherein the pH of saidcomposition is adjusted to a valve in the range of 4.5 to 6.5.
 3. Thepharmaceutical composition of claim 1 which contains 0.5 to 1.5 mg/g ofa lipophilic steroid drug selected from mometasone furoate,betamethasone diproprionate, betamethasone valerate, alcolomethasonediproprionate, hydrocortisone and mixtures thereof.
 4. Thepharmaceutical composition of claim 1 which contains 5 to 15 mg/g of alipophilic antifungal drug.
 5. The pharmaceutical composition of claim 1which contains 0.5 to 1.5 mg/g of a lipophilic steroid drug selectedfrom mometasone furoate, betamethasone diproprionate, betamethasonevalerate, alcomethasone diproprionate, hydrocortisone and mixturesthereof and 5 to 15 mg/g of a lipophilic antifungal drug.
 6. Thepharmaceutical composition of claim 2 which contains 0.5 to 1.5 mg/g ofa lipophilic steroid drug selected from mometasone furoate,betamethasone diproprionate, betamethasone valerate, alcolomethasonediproprionte, hydrocortisone and mixtures thereof.
 7. The pharmaceuticalcomposition of claim 2 which contains 5 to 15 mg/g of a lipophilicantifungal drug.
 8. The pharmaceutical composition of claim 2 whichcontains 0.5 to 1.5 mg/g of a lipophilic steroid drug selected frommometasone furoate, betamethasone diproprionate, betamethasone valerate,alcomethasone diproprionate, hydrocortisone and mixtures thereof and 5to 15 mg/g of a lipophilic antifungal drug.
 9. A topical creampharmaceutical composition of claim 1, which comprises:a. 0.5 to 2.0mg/g of at least one lipophilic steroid or antifungal drug; b. 35 mg/gof diethyl sebacate or mineral oil; c. 150 mg/g of white petrolatum; d.40 mg/g of propylene glycol stearate; e. 55 mg/g of a mixture of stearylalcohol and Ceteareth-20; f. 10 mg/g of trimethylsiloxy-silicate; g. 50mg/g of propylene glycol; h. 10 mg/g of benzyl alcohol; and i. 50 mg/gof N-methyl-2-pyrrolidone; j. q.s. of purified water to 1 g; and whereinthe pH of said composition is adjusted to a value in the range of 4.5 to6.5.
 10. A topical lotion pharmaceutical composition of claim 2 whichcomprises:a. 0.5 to 2.0 mg/g of at least one lipophilic steroid orantifungal drug; b. 35 mg/g of diethyl sebacate or mineral oil; c. 100mg/g of white petrolatum; d. 25 mg/g of propylene glycol stearate; e. 25mg/g of a mixture of stearyl alcohol and Ceteareth-20; f. 10 mg/g oftrimethylsiloxy-silicate; g. 50 mg/g of propylene glycol; h. 10 mg/g ofbenzyl alcohol; and i. 50 mg/g of N-methyl-2-pyrrolidone j. q.s. mg/g ofpurified water to 1 g; and wherein the pH of said composition isadjusted to a valve in the range of 4.5 to 6.5.